Antigenic variation of cloned Plasmodium fragile in its natural host Macaca sinica. Sequential appearance of successive variant antigenic types.

Handunnetti, SM; Mendis, Kamini; David, Peter H.

doi:10.1084/jem.165.5.1269

Cited by 114 publications

(65 citation statements)

References 17 publications

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“…Loss of infectivity to mosquitoes during crisis (day [5][6][7][8][9][10] in a P. cynomolgi infection in a toque monkey as shown by : the direct infectivity of the infected toque monkey to mosquitoes ("); and the intrinsic infectivity of the gametocyte-infected blood fed to mosquitoes through a membrane in the presence of nonimmune NMS (EW) in relation to the total parasitemia (0) and gametocyternia (*) on each day of the infection. Comparable results were obtained in all of the seven animals studied.…”

Section: Resultsmentioning

confidence: 99%

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Cytokines kill malaria parasites during infection crisis: extracellular complementary factors are essential.

Naotunne

Karunaweera

Giudice

et al. 1991

The Journal of Experimental Medicine

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126

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SummaryMalaria infection crisis, at which the parasitemia drops precipitously and the parasite loses infectivity to the mosquito vector, occurs in many natural malaria systems, and has not been explained. We demonstrate that in a simian malaria parasite (Plasmodium cynomolgi in its natural host, the toque monkey), 'the loss of infectivity during crisis is due to the death of circulating intraerythrocytic gametocytes mediated by crisis serum . These parasite-killing effects in crisis serum are due to the presence in the serum of cytokines tumor necrosis factor and interferon y, which are produced by the host as a result of the malaria infection . The killing activity of each cytokine is absolutely dependent upon the presence of additional, as yet unidentified factor(s) in the crisis serum . nfectivity of malarial infections to mosquitoes is due to the presence of circulating gametocytes, the sexual stages that fertilize in the midgut o£ a blood-fed mosquito. In several malaria host-parasite systems, it has been noted that peaks of parasitemia are associated with "crisis" in the infection (1-3) and the simultaneous reduction or loss of infectivity of the parasite to mosquitoes (4, 5); neither of these phenomena has been explained . During a blood infection of Plasmodium cynomolgi in its natural host, the toque monkey, Macaca sinica, peak parasitemia is often accompanied by a crisis in the infection; this is most pronounced in splenectomized animals and is characterized by the appearance of morphologically abnormal intraerythrocytic parasites. At crisis, there is a sudden loss of infectivity of the parasites to mosquitoes, which persists for 5 to 7 days. We show here that the loss of infectivity at crisis is due to death of circulating intraerythrocytic gametocytes mediated by crisis serum . These killing effects in the crisis serum are due to the presence of the cytokines TNF and IFN-y ; the killing activity of each cytokine is absolutely dependent upon the presence of additional, as yet unidentified, factor(s) in the crisis serum . Materials and MethodsAnimals. The toque monkey, Macaca sinica, the natural host ofP. cynomolgi ceylonensis, was used in this study. Wild-caught adult animals of either sex, weighing between 1 and 4 kg, which were free of malaria infections as determined by the indirect immunofluorescence test, were used for experiments. Splenectomies were performed using standard sterile techniques as previously described (6) .

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Section: Resultsmentioning

confidence: 99%

“…Wild-caught adult animals of either sex, weighing between 1 and 4 kg, which were free of malaria infections as determined by the indirect immunofluorescence test, were used for experiments. Splenectomies were performed using standard sterile techniques as previously described (6) .…”

Section: Methodsmentioning

confidence: 99%

Cytokines kill malaria parasites during infection crisis: extracellular complementary factors are essential.

Naotunne

Karunaweera

Giudice

et al. 1991

The Journal of Experimental Medicine

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126

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“…Like cytoadherence, perhaps the most compelling evidence that antigenic variation confers a fitness advantage is its prevalence throughout the Plasmodium genus. Evidence for antigenic variation exists in all species of parasite studied (P. berghei (Cox 1962); P. knowlesi (Brown & Brown 1965); P. cynomolgi (Voller & Rossan 1969); P. falciparum Biggs et al 1991;Roberts et al 1992); P. chabaudi (McLean et al 1982); P. fragile (Handunetti et al 1987); and probably P. vivax del Portillo et al 2001)). Different sets of genes are responsible in different species (Howard & Barnwell 1985;al-Khedery et al 1999;del Portillo et al 2001;Janssen et al 2001Janssen et al , 2002, suggesting convergent evolution for this phenotype.…”

Section: (B) Antigenic Variationmentioning

confidence: 99%

“…Only the first of these hypotheses is supported by experimental evidence, and this is largely indirect. The main source of evidence is the observation from animal models that the parasite's expression of cytoadherence and/or associated variant antigens is downregulated in splenectomized animals (see Hommel et al 1983;David et al 1983;Barnwell et al 1983a,b;Langreth & Peterson 1985;Handunetti et al 1987;Gilks et al 1990). This suggests that in the absence of the spleen, expression of these proteins on the surface of the red blood cell is costly to the parasite, but is maintained in spleen-intact animals because of the fitness advantage that it incurs.…”

Section: Molecular Mechanisms For Virulence In Relation To Parasite Fmentioning

confidence: 99%

Virulence in malaria: an evolutionary viewpoint

Mackinnon

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2004

Phil. Trans. R. Soc. Lond. B

225

205

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Malaria parasites cause much morbidity and mortality to their human hosts. From our evolutionary perspective, this is because virulence is positively associated with parasite transmission rate. Natural selection therefore drives virulence upwards, but only to the point where the cost to transmission caused by host death begins to outweigh the transmission benefits. In this review, we summarize data from the laboratory rodent malaria model, Plasmodium chabaudi, and field data on the human malaria parasite, P. falciparum, in relation to this virulence trade-off hypothesis. The data from both species show strong positive correlations between asexual multiplication, transmission rate, infection length, morbidity and mortality, and therefore support the underlying assumptions of the hypothesis. Moreover, the P. falciparum data show that expected total lifetime transmission of the parasite is maximized in young children in whom the fitness cost of host mortality balances the fitness benefits of higher transmission rates and slower clearance rates, thus exhibiting the hypothesized virulence trade-off. This evolutionary explanation of virulence appears to accord well with the clinical and molecular explanations of pathogenesis that involve cytoadherence, red cell invasion and immune evasion, although direct evidence of the fitness advantages of these mechanisms is scarce. One implication of this evolutionary view of virulence is that parasite populations are expected to evolve new levels of virulence in response to medical interventions such as vaccines and drugs.

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“…falciparum parasites express var genes in a mutually exclusive fashion (5). However, while multiple var genes may be expressed by different parasites within a host at any one time, the dynamics of infections are characterized by sequential waves of parasitemia that are dominated by the expression of a specific var gene (6)(7)(8). The decrease in frequency of expression of a particular var gene is associated with the production of antibodies specific to that var gene product, PfEMP1.…”

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confidence: 99%

Cross-Reactive Immune Responses as Primary Drivers of Malaria Chronicity

et al. 2014

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The within-host dynamics of an infection with the malaria parasite Plasmodium falciparum are the result of a complex interplay between the host immune system and parasite. Continual variation of the P. falciparum erythrocyte membrane protein (PfEMP1) antigens displayed on the surface of infected red blood cells enables the parasite to evade the immune system and prolong infection. Despite the importance of antigenic variation in generating the dynamics of infection, our understanding of the mechanisms by which antigenic variation generates long-term chronic infections is still limited. We developed a model to examine the role of cross-reactivity in generating infection dynamics that are comparable to those of experimental infections. The hybrid computational model we developed is attuned to the biology of malaria by mixing discrete replication events, which mimics the synchrony of parasite replication and invasion, with continuous interaction with the immune system. Using simulations, we evaluated the dynamics of a single malaria infection over time. We then examined three major mechanisms by which the dynamics of a malaria infection can be structured: cross-reactivity of the immune response to PfEMP1, differences in parasite clearance rates, and heterogeneity in the rate at which antigens switch. The results of our simulations demonstrate that cross-reactive immune responses play a primary role in generating the dynamics observed in experimentally untreated infections and in lengthening the period of infection. Importantly, we also find that it is the primary response to the initially expressed PfEMP1, or small subset thereof, that structures the cascading cross-immune dynamics and allows for elongation of the infection.

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Antigenic variation of cloned Plasmodium fragile in its natural host Macaca sinica. Sequential appearance of successive variant antigenic types.

Cited by 114 publications

References 17 publications

Cytokines kill malaria parasites during infection crisis: extracellular complementary factors are essential.

Cytokines kill malaria parasites during infection crisis: extracellular complementary factors are essential.

Virulence in malaria: an evolutionary viewpoint

Cross-Reactive Immune Responses as Primary Drivers of Malaria Chronicity

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